A family study of asymptomatic small bowel Crohn's disease

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DigestiveandLiverDisease46(2014)276–278

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Digestive

and

Liver

Disease

j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Short

Report

A

family

study

of

asymptomatic

small

bowel

Crohn’s

disease

夽

Livia

Biancone

a,∗

_,

_Emma

_Calabrese

a

_,

_Carmelina

_Petruzziello

a

_,

_Alessandra

_Capanna

a

_,

Francesca

Zorzi

a

_,

_Sara

_Onali

a

_,

_Giovanna

_Condino

a

_,

_Elisabetta

_Lolli

a

_,

_Cinzia

_Ciccacci

b

_,

Paola

Borgiani

b

_,

_Francesco

_Pallone

a

a_GI_Unit,_Department_of_Systems_Medicine,_University_of_Tor_Vergata,_Rome,_Italy b_Department_of_Biomedicine_and_Prevention,_University_of_Tor_Vergata,_Rome,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received1April2013 Accepted6November2013 Availableonline17December2013 Keywords:

AsymptomaticCD Crohn’sdisease(CD) Familystudy

SmallIntestineContrastUltrasonography (SICUS)

a

b

s

t

r

a

c

t

Background:DiscrepanciesbetweenseverityoflesionsandsymptomsmaybeobservedinCrohn’sdisease.

WeprospectivelyassessedwhetherCrohn’sdiseasemaybediagnosedamongasymptomaticrelativesof

patients,usingSmallBowelContrastUltrasonography.

Methods:DiagnosisofasymptomaticCrohn’sdiseaserelativeswasdeﬁnedultrasonographicallyas:bowel

wallthickness>3mm,boweldilation/stricture,lumendiameter>2.5cm.Diagnosiswasconﬁrmedby

ileocolonoscopy.SubjectswerealsoscreenedfortheLeu3020insCmutation.

Results:Consentwasgivenby35asymptomaticﬁrst-degreerelativesof18Crohn’sdiseasepatients.

Ultrasonographyindicatedincreasedbowelwallthickness(5mm)compatiblewithilealCrohn’sdisease

in1relative(2.8%),a42year-oldmale.Ileocolonoscopy,histology,andradiologyconﬁrmedthe

diag-nosisofstricturingilealCrohn’sdisease.Gallbladderstonesweredetectedin7/35(20%)relativesand

Leu3020insCmutationin3/35(8.5%).

Conclusions:SmallBowelContrastUltrasonographymaybeausefultooltodiagnoseasymptomaticsmall

bowelCrohn’sdiseaseamongﬁrst-degreerelativesofpatients.

1. Introduction

In Crohn’s Disease (CD) discrepancies between severity of lesions and symptoms may be observed [1]; furthermore the incidenceand prevalenceof CD is higher within family groups [1,2].

SmallBowelContrast Ultrasonography(SICUS)performedby an experienced physician shows high accuracy for visualizing small bowel lesions in CD [3–5]; therefore we performed a prospective study to assess whether small bowel CD can be diagnosed in asymptomatic CD relatives by using SICUS as a screeningtechnique.Conventionalendoscopicandradiologic anal-yses were then performed for relatives with SICUS ﬁndings compatible with CD. Asymptomaticconditions associated with smallbowelCD(kidney/gallbladderstones)werealsoassessedby ultrasound.

夽 Grantsupport:Thestudywassupportedby:FondazioneUmbertodiMario,Largo Marchiafava,00161,Roma;PRIN2008;Codicen.2008X8NRH4.

∗ Correspondingauthorat:CattedradiGastroenterologia,Dipartimentodi Medi-cinaInterna,UniversitàdiRoma“TorVergata”,ViaMontpellier,1,00133Rome,Italy. Tel.:+390672596376;fax:+390620903738.

E-mailaddress:biancone@med.uniroma2.it(L.Biancone).

2. Materialsandmethods

2.1. Studyprotocol

InthisprospectivelongitudinalstudyCDpatientsreferringto ourtertiaryIBD referralcentrewereaskedtoenrol ina family studyaimedatscreeningforasymptomaticCD.Compliant asymp-tomaticrelatives,includingcompletefamilygroupsofCDpatients wereenrolled(firstdegreerelatives,possibly allsiblingsofthe affectedfamily member,and allchildren >18years). Compliant relativeswerescreenedforbothsmallbowelCD,bySICUS,andfor theCARD15(Leu3020insC)mutation.IncaseofSICUSfindings com-patiblewithCD,ileocolonoscopywithbiopsieswasperformed.The presenceofasymptomaticconditionsassociatedwithsmallbowel CD(kidney/gallbladderstones)wasalsoassessedbyultrasound. ThestudywasapprovedbythelocalEthicalCommitteeandeach relativefilledupawritteninformedconsenttobetestedforNOD2 mutations.

2.2. CDrelatives

Inclusioncriteriawere:(1)beingﬁrstdegreerelativeofaCD patientinfollow-up;(2)agebetween18and75years;nohistory of inﬂammatory bowel disease (IBD) or other gastrointestinal diseases;(3)nohistoryofgastrointestinalsymptomsorintestinal

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L.Bianconeetal./DigestiveandLiverDisease46(2014)276–278 277

surgery (appendectomy allowed); (4) handing in the written informed consent. Exclusion criteria were: having performed smallbowelimagingorcolonoscopyduringthelast5years;severe comorbidities;obesity. At enrolment,a detailed clinical history and physical examination excluded any sign and/or symptom compatiblewithCD.

2.3. SICUS

SICUS was performed by an experienced gastroenterologist [2–6].FindingscompatiblewithsmallbowelCDincluded[2,6]:(1) increasedbowelwallthickness(BWT>3mm);(2)“stiffloop”;(3) smallboweldilation(lumendiameter>2.5cm);(4)bowelstricture (diameter<1cm)atthelevelofmaximallydistendedloop;(5) ﬁs-tulae;(6)mesentericenlargementand/ormasses;(7)lymphnodes enlargement(>1cm);(8)abscesses.

2.4. Colonoscopy

Ileocolonoscopywithbiopsywasperformedbyadedicated gas-troenterologist[6]inrelativesshowingSICUSﬁndingscompatible withCD.

2.5. CARD15mutation

Blood samples were collected from each of the compliant unaffected relatives in EDTA tubes (5ml). The presence of the Leu3020insCmutationwasthendetermined[7].

2.6. Statisticalanalysis

Demographiccharacteristics and ﬁndings wereexpressedas median(range)orpercentages.

3. Results

Fifty-ﬁveconsecutiveCD patients(26 males,median age45 years, range17–79 years)were eligibletobeenrolled.Written consenttoparticipatewasgivenby18/55(32%)CDpatients(13 males;medianage30,range17–68;medianageatdiagnosis23; range16–67;CDsite:ileumn=6;neo-terminalileumn=9; ileum-colonn=3).Amongthese18 CDfamilygroups, writtenconsent wasobtainedby35oftheirasymptomaticrelatives.Themain rea-sonsforrefusingconsentwereanxiety/feartobescreenedforCD, orlongdistancefromthereferralcentre.Thegradeof relation-shipbetweenpatientsandfamilymembersincludedﬁrst-degree relatives(4fathers,5mothers,8sons;5daughters,5brothers,8 sisters).

SICUSdetectedsmallbowellesionscompatiblewithCD in1 (2.85%)asymptomaticrelative.AnincreasedBWT(5mm)ofthe distalileum(Fig.1a)wasobservedwithSICUS ina 42-year-old man(whosemotherhadfibrostricturingilealCD).Ileocolonoscopy (Fig.1b),histology,andsmallbowelfollowthrough(Fig.1c) con-firmedthediagnosisofilealCD,showingdeepulcersandamarked ulceratedstenosis of thedistal ileum,withileal dilation above stenosis.Nogastrointestinalsymptomsorlaboratoryalterations weredetected.Clinicalassessmentperformedby3independent dedicatedgastroenterologistsconfirmedtheabsenceof gastroin-testinalsymptoms.ThisCDrelativeshowingileallesionsappeared healthyandshowednonutritionaldefects(BMI28),norhistory ofpresentorpastgastrointestinalsymptoms.Abdominal exami-nationwasnegative.Afterinformeddiscussionwiththepatient, mesalamine(2.4g/day) wasgiven, andnosymptomsdeveloped over2yearsoffollow-up.

None of the remaining 34 relatives considered showed an increased BWT. After SICUS, one additional asymptomatic

Fig.1. (Panelsa–c)Imagesofthedistalileuminanasymptomatic42-year-old manwithfamilialCD(motherwithﬁbrostricturingilealCD),asassessedbySmall IntestineContrastUltrasonography(SICUS)(panela),ileocolonoscopy(panelb)and smallbowelfollowthrough(SBFT)(panelc).Panela:SICUSshowsanincreased BWT(5mm;n.v.≤3mm)ofthedistalileum(arrow),compatiblewithCD.Panelb: Ileocolonoscopyshowsdeepulcerationssurroundedbyseverelyinﬂamedmucosa inthedistalileumandileo-cecalvalve,compatiblewithCD;Panelc:SBFTshows deepulcersandoneulceratedstrictureofthedistalileum(arrow),associatedwith amarkeddilationabovestenosis.

relative (male, age18 years, whose father had jejuno-ileal CD) referred bloody stools (spontaneously resolved in few days). Ileocolonoscopy after bleeding detected a small rectal polyp (hyperplastic)andaphtoidulcersintheileum.Capsuleendoscopy (SBCE)detectedmultipleapthoid ulcersinthesmallboweland mesalazine(2.4g/day)wasgiven.Noclinicalorhaematochemical alterations were detected. The patient appeared healthy, with nohistoryofnonsteroidalantiinﬂammatorydrugs(NSAIDs)use, smoking,or appendectomy.After2 years,ileocolonoscopy with biopsiesshoweddeepulcerationsinthedistalileumcompatible withCD.

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278 L.Bianconeetal./DigestiveandLiverDisease46(2014)276–278

Amongthe35asymptomaticrelativesstudiedbyultrasound, noneshowed kidney stones, while 7 (20%) showed previously undetectedgallbladderstones.

3.1. CARD15mutation

TheLeu3020insCmutationwasobservedin heterozygosisin 3/35(8.5%) relatives,all 3 showingnosmall bowel lesions.No Leu3020insCmutationwasdetectedinthe2relativesshowing CD-relatedsmallbowellesions.CARD15genemutationanalysisalso showedthat2/15CDcompliantpatientswereheterozygotesand nonewashomozygoteforthismutation.

4. Discussion

InCD,discrepanciesbetweenseverityofthelesionsandclinical coursemaybeobserved[1].Earlyendoscopicrecurrenceisoften asymptomatic,thusindicatingthatCDlesionsmaydevelopwith nosymptoms[8].Nevertheless,severeendoscopicrecurrenceat1 yearispredictiveofclinicalrelapse[9],thussupportingthatearly detectionofasymptomaticlesionsmayhelptopreventrelapse. Withthis purpose,immunomodulatorsareindicatedin inactive CDpatientswithsevereendoscopicrecurrence[10].Theincreasing useofileocolonoscopyisexpandingthenumberofobservedileal lesionscompatiblewithCDinasymptomaticsubjects[11]. Find-ingscompatiblewithulcerativecolitishavealsobeenreportedin asymptomaticsubjects[12].WhetherthesecasesrefertoIBDor otherconditionsiscurrentlyundeﬁned.

These observations prompted us to assess, in a prospective study,whetherCDmaybediagnosedinasymptomaticCD rela-tives. The recruitment rate was quite low (32%), despite the enrolledpatientsbeingunderregularfollow-up.SearchingforCDin asymptomaticrelativesmayindeedinduceadditionalfear/anxiety present due to the CD diagnosis in their family member. In thepresent preliminaryobservation, ileal CD wasdiagnosed in an adult male with no history of abdominal symptoms. The smallcohort sizerepresentsthemain limitationof thepresent preliminaryobservation, thusnot allowinga generalstatement regarding the prevalence of CD in asymptomatic CD relatives. Furthermore,duetothelimitednumber oftestedrelatives,the impactof NOD2 testing cannot beevaluated. Nevertheless,the ratioof asymptomatic CD diagnosed in ourpopulationof rela-tives was quite high (1/35 relatives, 2.85%). Asymptomatic CD hasbeen reported in a higher proportion of asymptomatic CD relatives(4/17;23%)byusingtheintestinalpermeabilitytest con-ﬁrmedbyileocolonoscopy[13].AsymptomaticIBDhasalsobeen reportedinfewstudiesusingclinical[14]orlaboratoryparameters [12].

Inourstudy,oneadditionalasymptomaticrelativewitha nor-malSICUSdevelopedbloodystoolsafterenrolment.SmallbowelCD wasdiagnosedbyusingileocolonoscopyandSBCE.Asbloodystools developedafterSICUS,thiscase wasreportedbutwasexcluded fromtheanalysis,thusconsideringonlyasymptomaticrelatives. AnearlierdiagnosisratherthanapossibleasymptomaticIBDmay explainthepresentcaseaswellaspreviousﬁndings[11–14].

Thelimitednumberofrelativestestedrepresentsthemain limi-tationofthestudy.Duetothelowsamplesize,theimpactofNOD2 testingcouldnotbeevaluated.Inthepresentstudy,onlyoneof theNOD2variants(Leu3020insC)wasinvestigated.Inourprevious studyinCDpatientsreferringtothesameIBDUnit[7],weindeed reportedthatonlytheLeu1007fsinsCmutation(nottheArg702Trp, Gly908Arg)appearedtobeariskfactorforCD.

Superﬁcial lesions of the ileum have also been reported in asymptomatic individuals undergoing colonoscopy for non-IBD relatedconditions[11].Nevertheless,onlyaminorityofpatients (0.67%)appeartodevelopCDinthelongterm,includingpatients not using NSAIDs [11]. Isolated asymptomatic ileitis has been reportedtonotprogresstoovertCDinthelongterm,despite fea-turesofchronicityinilealbiopsies[15].Duringa2-yearfollow-up, gastrointestinalsymptomsattimeofileocolonoscopyappearedthe bestpredictorofprogressiontoCDinisolatedileitis(p<0.001)[15]. Acarefulevaluationisthereforerequiredbeforeconsideringa diag-nosisofCDinasymptomaticindividualsshowinganunexpected ileitis.Potentialissueswhensearchingforasymptomaticlesions includethepossibleclinicalimplications.Afterdetailedinformed discussionwiththepatient,mesalaminewasgivenalsoin rela-tiontoitspossiblechemopreventiverole[10].Whethertreating asymptomaticCDpatientsmaymodifythenaturalhistoryofthe diseaseis still unknown [16]. Nevertheless,we do believe that studiesscreeningforasymptomaticCDbyusingnon-invasive tech-niquesmayhelpdeﬁnethenaturalhistoryofthedisease.

Conﬂictofinterest

Theauthorsdeclarenoconﬂictofinterest.

References

[1]CosnesJ,Gower-RousseauC,SeksikP,etal.Epidemiologyandnaturalhistory ofinﬂammatoryboweldiseases.Gastroenterology2011;140:1785–94.

[2]MolodeckyNA,SoonIS,RabiDM,etal.Increasingincidenceandprevalence oftheinﬂammatoryboweldiseaseswithtime,basedonsystematicreview. Gastroenterology2012;142:46–54.

[3]CalabreseE,LaSetaF,BuccellatoA,etal.Crohn’sDisease:acomparative prospectivestudyoftransabdominalultrasonography,smallintestine con-trastultrasonographyandsmallbowelenema.InﬂammatoryBowelDiseases 2005;11:139–45.

[4]CalabreseE,PetruzzielloC,OnaliS,etal.Severityofpostoperativerecurrence inCrohn’sDisease:correlationbetweenendoscopicandsonographicﬁndings. InﬂammatoryBowelDiseases2009;15:1635–42.

[5]CalabreseE,ZorziF,ZuzziS,etal.Developmentofanumericalindex quanti-tatingsmallboweldamageasdetectedbyultrasonographyinCrohn’sdisease. JournalofCrohn’sandColitis2012;6:852–60.

[6]BianconeL,CalabreseE,PetruzzielloC,etal.Wirelesscapsuleendoscopyand smallintestinecontrastultrasonographyinrecurrenceofCrohn’sDisease. InﬂammatoryBowelDiseases2007;13:1256–65.

[7]Vavassori P, Borgiani P,Biancone L, et al. CARD15 mutation analysisin anItalianpopulation:Leu1007fsinsCbutneitherArg702TrpnorGly908Arg mutationsareassociatedwithCrohn’sdisease.InﬂammatoryBowelDiseases 2004;10:116–21.

[8]Rutgeerts P,Geboes K,VantrappenG, etal. Natural history ofrecurrent Crohn’sdiseaseattheileocolonicanastomosisaftercurative surgery.Gut 1984;25:665–72.

[9]RutgeertsP,GeboesK,VantrappenG,etal.Predictabilityofthepostoperative courseofCrohn’sDisease.Gastroenterology1990;99:956–63.

[10]VanAsscheG,DignassA,ReinischW,etal.ThesecondEuropean evidence-basedconsensusonthediagnosisandmanagementofCrohn’sdisease:special situations.JournalofCrohn’sandColitis2010;4:63–101.

[11]ChangHS,LeeD,KimJC,etal.Isolatedterminalilealulcerationsin asymp-tomaticindividuals:naturalcourseandclinicalsigniﬁcance.Gastrointestinal Endoscopy2010;72:1226–32.

[12]SakataT,NiwaY,GotoH,etal.Asymptomaticinﬂammatoryboweldiseasewith specialreferencetoulcerativecolitisinapparentlyhealthypersons.American JournalofGastroenterology2001;96:735–9.

[13]Parrilli G, Orsini L, Corsaro M, et al. Is intestinal permeability test useful for asymptomatic Crohn’s disease? Inﬂammatory Bowel Diseases 2006;12:1189–90.

[14]GalbraithSS,DroletBA,KugathasanS,etal. Asymptomaticinﬂammatory boweldiseasepresentingwithmucocutaneousﬁndings.Pediatrics2005;116: 439–44.

[15]Courville EL, Siegel CA, Vay T, et al. Isolated asymptomatic ileitis does notprogresstoovertCrohn’sdiseaseonlong-termfollow-updespite fea-turesofchronicityinilealbiopsies.AmericanJournalofSurgicalPathology 2009;33:1341–7.

[16]HedinCR,StaggAJ,WhelanK,etal.FamilystudiesinCrohn’sdisease:new horizonsinunderstandingdiseasepathogenesis,riskandprevention.Gut 2012;61:311–8.